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Deletion of GSK3? in D2R-expressing neurons reveals distinct roles for ?-arrestin signaling in antipsychotic and lithium action.

ABSTRACT: Several studies in rodent models have shown that glycogen synthase kinase 3 ? (GSK3?) plays an important role in the actions of antispychotics and mood stabilizers. Recently it was demonstrated that GSK3? through a ?-arrestin2/protein kinase B (PKB or Akt)/protein phosphatase 2A (PP2A) signaling complex regulates dopamine (DA)- and lithium-sensitive behaviors and is required to mediate endophenotypes of mania and depression in rodents. We have previously shown that atypical antipsychotics antagonize DA D2 receptor (D2R)/?-arrestin2 interactions more efficaciously than G-protein-dependent signaling, whereas typical antipsychotics inhibit both pathways with similar efficacy. To elucidate the site of action of GSK3? in regulating DA- or lithium-sensitive behaviors, we generated conditional knockouts of GSK3?, where GSK3? was deleted in either DA D1- or D2-receptor-expressing neurons. We analyzed these mice for behaviors commonly used to test antipsychotic efficacy or behaviors that are sensitive to lithium treatment. Mice with deletion of GSK3? in D2 (D2GSK3?(-/-)) but not D1 (D1GSK3?(-/-)) neurons mimic antipsychotic action. However, haloperidol (HAL)-induced catalepsy was unchanged in either D2GSK3?(-/-) or D1GSK3?(-/-) mice compared with control mice. Interestingly, genetic stabilization of ?-catenin, a downstream target of GSK3?, in D2 neurons did not affect any of the behaviors tested. Moreover, D2GSK3?(-/-) or D1GSK3?(-/-) mice showed similar responses to controls in the tail suspension test (TST) and dark-light emergence test, behaviors which were previously shown to be ?-arrestin2- and GSK3?-dependent and sensitive to lithium treatment. Taken together these studies suggest that selective deletion of GSK3? but not stabilization of ?-catenin in D2 neurons mimics antipsychotic action without affecting signaling pathways involved in catalepsy or certain mood-related behaviors.

SUBMITTER: Urs NM

PROVIDER: S-EPMC3528495 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Deletion of GSK3β in D2R-expressing neurons reveals distinct roles for β-arrestin signaling in antipsychotic and lithium action.

Urs Nikhil M NM Snyder Joshua C JC Jacobsen Jacob P R JP Peterson Sean M SM Caron Marc G MG

Proceedings of the National Academy of Sciences of the United States of America 20121127 50

Several studies in rodent models have shown that glycogen synthase kinase 3 β (GSK3β) plays an important role in the actions of antispychotics and mood stabilizers. Recently it was demonstrated that GSK3β through a β-arrestin2/protein kinase B (PKB or Akt)/protein phosphatase 2A (PP2A) signaling complex regulates dopamine (DA)- and lithium-sensitive behaviors and is required to mediate endophenotypes of mania and depression in rodents. We have previously shown that atypical antipsychotics antago ...[more]

PMID: 23188793

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Project description:BackgroundFor decades, the dopamine D2 receptor (D2R) has been known as the main target of antipsychotic medications, but the mechanism for antipsychotic effects beyond this pharmacological target remains unclear. Disrupted-in-schizophrenia 1 (DISC1) is a gene implicated in the etiology of schizophrenia, and we have found elevated levels of the D2R-DISC1 complex in the postmortem brain tissue of patients with schizophrenia.MethodsWe used coimmunoprecipitation to measure D2R-DISC1 complex levels in peripheral blood samples from patients with schizophrenia and unaffected controls in 3 cohorts (including males and females) from different hospitals. We also used label-free mass spectrometry to conduct proteomic analysis of these samples.ResultsLevels of the D2R-DISC1 complex were elevated in the peripheral blood samples of patients with schizophrenia from 3 independent cohorts, and were normalized with antipsychotic treatment. Proteomic analysis of the blood samples from patients with high D2R-DISC1 complex levels that were normalized with antipsychotic treatment revealed a number of altered proteins and pathways associated with D2R, DISC1 and the D2R-DISC1 complex. We identified additional proteins and pathways that were associated with antipsychotic treatment in schizophrenia, and that may also be novel targets for schizophrenia treatment.LimitationsSample sizes were relatively small, but were sufficient to detect associations between D2R-DISC1 levels, schizophrenia and treatment response. The relevance of leukocyte changes to the symptoms of schizophrenia is unknown. The coimmunoprecipitation lanes included several nonspecific bands.ConclusionLevels of the D2R-DISC1 complex were elevated in patients with schizophrenia and reduced with antipsychotic treatment. This finding reinforces the independent role of each protein in schizophrenia. Our results enhanced our understanding of the molecular pathways involved in schizophrenia and in antipsychotic medications, and identified novel potential molecular targets for treating schizophrenia.

Dataset Information

Deletion of GSK3? in D2R-expressing neurons reveals distinct roles for ?-arrestin signaling in antipsychotic and lithium action.

Publications

Deletion of GSK3β in D2R-expressing neurons reveals distinct roles for β-arrestin signaling in antipsychotic and lithium action.

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